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Nature Papers on CRISPR-Cas9 Gene Editing, HSC Development

New details about the mechanism by which DNA is unwound so that its target sequence can be read during CRISPR-Cas9 gene editing are reported in this week's Nature Structural & Molecular Biology. The study provides insights that may help in the development of improved genome editors. During CRISPR-Cas9 editing, Cas9 searches millions of DNA base pairs to locate a 20-nucleotide, guide RNA-complementary target sequence that abuts a protospacer-adjacent motif. This requires local unwinding to expose DNA nucleotides for RNA hybridization, but the mechanism behind this process is unknown. To investigate, University of California, Berkeley scientists use cryogenic-electron microscopy and other techniques to reveal the individual steps Cas9 during this phase of its genome-editing function: sharply bending and undertwisting DNA upon binding to a protospacer-adjacent motif, thereby flipping DNA nucleotides out of the duplex and toward the guide RNA for sequence interrogation. "These actions, repeated over and over, comprise the slowest phase of Cas9's" genome-editing role, the researchers write. "The energetic landscape surrounding the states identified in this work will be a crucial subject of study to understand the success of current state-of-the-art genome editors and to inform the engineering of faster ones."

A team led by scientists from the University of California, Los Angeles present in Nature this week a molecular map of hematopoietic stem cell (HSC) development in the human embryo. The work represents a new resource to help in the creation of fully functional HSCs in the lab. To date, efforts to understand human HSC development have been hampered by the inability to distinguish between HSCs and progenitors, and to identify their endothelial precursor. Using RNA sequencing and spatial transcriptomics, the researchers built an in vivo single-cell transcriptome map tracking of human hematopoietic tissues as they migrate through the body during different stages of development. They also identify molecular signatures that distinguish HSCs from progenitors at any stage of development and pinpoint the endothelial cells from HSCs originate. The map, the investigators write, "will help to uncover the correct instructions for generating fully functional HSCs in vitro."